Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Gastroenterology. 2021 Aug;161(2):592-607. doi: 10.1053/j.gastro.2021.04.042. Epub 2021 Apr 27.
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs.
Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC.
Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNT-induced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4α binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 5'untranslated region of TP53 in IBD-CRCs. As reported previously, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs.
Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.
炎症性肠病（IBD）是一种慢性、复发性炎症性疾病，与结直肠癌（CRC）的风险升高相关。IBD 相关结直肠癌（IBD-CRC）与散发性 CRC（sCRC）相比，可能代表了一种不同的肿瘤发生途径。我们的目的是通过多种高通量方法综合描述 IBD 相关的肿瘤发生，并将结果与 sCRC 的内部数据集进行比较。
对 31 例 IBD-CRC 患者的肿瘤和相应正常组织的新鲜冷冻和福尔马林固定组织样本进行全基因组测序、单核苷酸多态性阵列、RNA 测序、全基因组甲基化分析和免疫组织化学分析。
基于转录组的肿瘤亚型分类显示，IBD-CRC 中完全不存在与 WNT 信号相关的经典上皮肿瘤亚型，而是以富含间充质基质的亚型为主。AXIN2 和 RNF43 等 WNT 负调控因子在 IBD-CRC 中强烈下调，与 sCRC 相比，HNF4A 上的染色体增益较少，HNF4A 是 WNT 诱导的上皮-间充质转化（EMT）的负调节剂。仅在 sCRC 基因组中检测到 HNF4α 结合位点的低甲基化富集。参与粘膜免疫的 PIGR 和 OSMR 通过 IBD-CRC 中的表观遗传修饰失调。全基因组分析显示，IBD-CRC 中 TP53 5'非翻译区的非编码突变显著富集。如前所述，与 sCRC 相比，IBD-CRC 中 APC 和 KRAS 的体细胞突变较少。
WNT 通路失调的不同机制使 IBD-CRC 偏向间充质肿瘤亚型，这可能影响预后和治疗选择。OSMR 信号的增加可能有利于 IBD 患者间充质肿瘤的建立。
